Infection by hepatitis C virus (“HCV”) is a compelling human medical problem. HCV is recognized as the causative agent for most cases of non-A, non-B hepatitis, with an estimated human sero-prevalence of 3% globally [A. Alberti et al., “Natural History of Hepatitis C,” J. Hepatology, 31., (Suppl. 1), pp. 17–24 (1999)]. Nearly four million individuals may be infected in the United States alone [M. J. Alter et al., “The Epidemiology of Viral Hepatitis in the United States, Gastroenterol. Clin. North Am., 23, pp. 437–455 (1994); M. J. Alter “Hepatitis C Virus Infection in the United States,” J. Hepatology, 31., (Suppl. 1), pp. 88–91 (1999)]. Unfortunately, there are no broadly effective treatments for the debilitating progression of chronic HCV.
There are not currently any satisfactory anti-HCV agents or treatments. Until recently, the only established therapy for HCV disease was interferon treatment. However, interferons have significant side effects [M. A. Wlaker et al., “Hepatitis C Virus: An Overview of Current Approaches and Progress,” DDT, 4, pp. 518–29 (1999); D. Moradpour et al., “Current and Evolving Therapies for Hepatitis C,” Eur. J. Gastroenterol. Hepatol., 11, pp. 1199–1202 (1999); H. L. A. Janssen et al. “Suicide Associated with Alfa-Interferon Therapy for Chronic Viral Hepatitis,” J. Hepatol., 21, pp. 241–243 (1994); P. F. Renault et al., “Side Effects of Alpha Interferon,” Seminars in Liver Disease, 9, pp. 273–277. (1989)] and induce long term remission in only a fraction (˜25%) of cases [O. Weiland, “Interferon Therapy in Chronic Hepatitis C Virus Infection”, FEMS Microbiol. Rev., 14, pp. 279–288 (1994)]. Recent introductions of the pegylated forms of interferon (PEG-INTRON® and PEGASYS®) and the combination therapy of ribavirin and pegylated interferon (REBETROL®) have resulted in only modest improvements in remission rates and only partial reductions in side effects. Moreover, the prospects for effective anti-HCV vaccines remain uncertain.
The HCV nonstructural (NS) proteins are presumed to provide the essential catalytic machinery for viral replication. The HCV NS3 serine protease and its associated cofactor, NS4A, helps process all of the viral enzymes, and is thus considered essential for viral replication. This processing appears to be analogous to that carried out by the human immunodeficiency virus aspartyl protease, which is also involved in viral enzyme processing HIV protease inhibitors, which inhibit viral protein processing are potent antiviral agents in man, indicating that interrupting this stage of the viral life cycle results in therapeutically active agents. Consequently it is an attractive target for drug discovery.
Protease inhibitors and many other compounds comprise N-terminal capping groups. Such N-terminal capping, or protecting, groups are not limited to HCV protease inhibitors. Any peptidyl biologically active compound may have an N-terminal capping group. Similarly, many non-peptidyl (particularly peptidyl mimetic) compounds comprise the equivalent of an N-terminal capping group. Furthermore, a primary or secondary amine in any compound could be derivatized with a capping group. Accordingly, N-terminal capping groups are widely used. There is therefore a need for N-terminal capping groups (sometimes referred to as protecting or protective groups) and methods for making such groups.
A pyrrole-based capping group that is particularly useful has been described (WO 03/087092). This capping group is relatively complex. A disadvantage of relatively complex capping groups is that they may not be readily available commercially and/or may be difficult to synthesize. As is known, carboxylic acids are convenient precursors for such capping groups. Unfortunately, there are no safe, efficient, and/or large-scale methods for synthesizing the carboxylic acid precursors corresponding to these particularly useful capping groups (see, D. T. Kozhich et al., Zh. Organ. Khimii, 16 pp. 849–855–750 (1980); UDC 547, 745: 312; A. J. Robinson et al., J. Org. Chem. 66, pp. 4148–4152 (2001); H. Falk et al. Monatsh. Chemie, 104, pp. 925–923 (1973)).
Thus, there is a need for efficient synthetic routes to these carboxylic acid precursors of pyrrole-based capping groups.